Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterization

Antimicrobial resistance of Helicobacter pylori (Hp) threatens currently available treatment regimens and prompts the development of antimicrobial drugs against new bacterial targets. One such class of drugs is Hp-flavodoxin (Hp-fld) inhibitors, which target an essential metabolic pathway in Hp. The...

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Autores: Beyria, Lilha, Gourbeyre, Ophelie, Salillas, Sandra, Mahía, Alejandro, Díaz de Villegas, María Dolores, Aínsa, José Antonio, Sancho, Javier, Bousquet-Mélou, Alain, Ferran, Aude A.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Universidad de Zaragoza
Repositorio:Zaguán. Repositorio Digital de la Universidad de Zaragoza
OAI Identifier:oai:zaguan.unizar.es:131847
Acceso en línea:http://zaguan.unizar.es/record/131847
Access Level:acceso abierto
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spelling Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterizationBeyria, LilhaGourbeyre, OphelieSalillas, SandraMahía, AlejandroDíaz de Villegas, María DoloresAínsa, José AntonioSancho, JavierBousquet-Mélou, AlainFerran, Aude A.Antimicrobial resistance of Helicobacter pylori (Hp) threatens currently available treatment regimens and prompts the development of antimicrobial drugs against new bacterial targets. One such class of drugs is Hp-flavodoxin (Hp-fld) inhibitors, which target an essential metabolic pathway in Hp. The aim of this study was to characterize the effects of these inhibitors against Hp over time when used alone or combined with conventional antibiotics. Four benzoxadiazol-based fld inhibitors were initially tested for their in vitro potency, with compound IV displaying the highest efficacy. This compound was then combined with clarithromycin, metronidazole, amoxicillin, levofloxacin, and rifampicin in further experiments. Checkerboard assays indicated that compound IV exhibited additive activity when combined with these antibiotics. The study further investigated the time course of antibacterial effects by exposing a high inoculum of Hp to compound IV and each antibiotic, alone or in combination. At just four times the minimum inhibitory concentration, compound IV demonstrated bactericidal effects within 6 h. However, the regrowth of bacteria occurred between 24 and 48 h of exposure. Similar patterns of killing followed by regrowth were observed for conventional antibiotics alone. However, the addition of compound IV to the antibiotics clearly limited regrowth over 72 h. These findings suggest that compound IV can effectively eliminate spontaneous mutants that are resistant to conventional antibiotics or prevent new mutations during drug exposure. Hp-fld inhibitors, such as compound IV, hold promise as new drugs to be integrated into Hp infection treatment, potentially reducing the development of resistance and shortening the duration of treatment.2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://zaguan.unizar.es/record/131847reponame:Zaguán. Repositorio Digital de la Universidad de Zaragozainstname:Universidad de ZaragozaInglésinfo:eu-repo/grantAgreement/ES/DGA/E45-20Rinfo:eu-repo/grantAgreement/ES/MICINN/PID2019-107293GB-I00info:eu-repo/semantics/openAccessoai:zaguan.unizar.es:1318472026-05-29T13:59:51Z
dc.title.none.fl_str_mv Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterization
title Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterization
spellingShingle Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterization
Beyria, Lilha
title_short Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterization
title_full Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterization
title_fullStr Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterization
title_full_unstemmed Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterization
title_sort Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterization
dc.creator.none.fl_str_mv Beyria, Lilha
Gourbeyre, Ophelie
Salillas, Sandra
Mahía, Alejandro
Díaz de Villegas, María Dolores
Aínsa, José Antonio
Sancho, Javier
Bousquet-Mélou, Alain
Ferran, Aude A.
author Beyria, Lilha
author_facet Beyria, Lilha
Gourbeyre, Ophelie
Salillas, Sandra
Mahía, Alejandro
Díaz de Villegas, María Dolores
Aínsa, José Antonio
Sancho, Javier
Bousquet-Mélou, Alain
Ferran, Aude A.
author_role author
author2 Gourbeyre, Ophelie
Salillas, Sandra
Mahía, Alejandro
Díaz de Villegas, María Dolores
Aínsa, José Antonio
Sancho, Javier
Bousquet-Mélou, Alain
Ferran, Aude A.
author2_role author
author
author
author
author
author
author
author
description Antimicrobial resistance of Helicobacter pylori (Hp) threatens currently available treatment regimens and prompts the development of antimicrobial drugs against new bacterial targets. One such class of drugs is Hp-flavodoxin (Hp-fld) inhibitors, which target an essential metabolic pathway in Hp. The aim of this study was to characterize the effects of these inhibitors against Hp over time when used alone or combined with conventional antibiotics. Four benzoxadiazol-based fld inhibitors were initially tested for their in vitro potency, with compound IV displaying the highest efficacy. This compound was then combined with clarithromycin, metronidazole, amoxicillin, levofloxacin, and rifampicin in further experiments. Checkerboard assays indicated that compound IV exhibited additive activity when combined with these antibiotics. The study further investigated the time course of antibacterial effects by exposing a high inoculum of Hp to compound IV and each antibiotic, alone or in combination. At just four times the minimum inhibitory concentration, compound IV demonstrated bactericidal effects within 6 h. However, the regrowth of bacteria occurred between 24 and 48 h of exposure. Similar patterns of killing followed by regrowth were observed for conventional antibiotics alone. However, the addition of compound IV to the antibiotics clearly limited regrowth over 72 h. These findings suggest that compound IV can effectively eliminate spontaneous mutants that are resistant to conventional antibiotics or prevent new mutations during drug exposure. Hp-fld inhibitors, such as compound IV, hold promise as new drugs to be integrated into Hp infection treatment, potentially reducing the development of resistance and shortening the duration of treatment.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
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status_str publishedVersion
dc.identifier.none.fl_str_mv http://zaguan.unizar.es/record/131847
url http://zaguan.unizar.es/record/131847
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/ES/DGA/E45-20R
info:eu-repo/grantAgreement/ES/MICINN/PID2019-107293GB-I00
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv
publisher.none.fl_str_mv
dc.source.none.fl_str_mv reponame:Zaguán. Repositorio Digital de la Universidad de Zaragoza
instname:Universidad de Zaragoza
instname_str Universidad de Zaragoza
reponame_str Zaguán. Repositorio Digital de la Universidad de Zaragoza
collection Zaguán. Repositorio Digital de la Universidad de Zaragoza
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